GDNF转基因成纤维细胞脑内移植治疗帕金森病大鼠模型

AN EXPERIMENTAL STUDY ON GENE THERAPY OF PARKINSON'S DISEASE RAT MODEL BY GRAFTING GDNF GENETICALLY- ENGINEERED PRIMARY FIBROBLASTS

为了观察表达胶质细胞系源性神经营养因子 (GDNF)的基因工程细胞在脑内移植后对帕金森病大鼠的治疗作用 ,将 6-羟基多巴胺脑内定位单侧 (损伤侧 )注射制备大鼠帕金森病模型。随机将动物分为实验组 (2 0只 )和对照组 (15只 ) ,分别植入GDNF和 Lac Z转基因的原代培养大鼠成纤维细胞于损伤侧纹状体内 ,动态观察动物单侧旋转行为以及多巴胺及其代谢产物 3 ,4-二羟苯乙酸和高香草酸含量的变化。结果表明 :实验组帕金森病大鼠单侧旋转行为明显减少 ,为移植前旋转圈数的 (64 .8± 5 .8) % (P<0 .0 5 ) ;其纹状体内多巴胺含量显著提高 ,恢复至移植前水平的 (14 .5± 2 .2 ) % (P<0 .0 5 ) ,而对照组仅为 (1.92± 0 .15 ) % ;转基因细胞在脑内可存活 1年以上。本研究结果提示 GDNF基因治疗对大鼠帕金森病具有潜在的临床应用价值。

The improvement of motor abnormalities and striatal levels of dopamine and its metabolites were observed by intracerebrally grafting primary fibroblasts genetically modified to produce glial cell line derived neurotrophic factor(GDNF)in a rat model of Parkinson's disease(PD). 6 OHDA was stereostactically injected into the striatum of the rats to induce a rat model of PD. The injuried rats were randomly divided into the experimental and the control group. The primary fibroblasts modified to produce GDNF and Lac Z were ipsilaterally implanted into the striatum of PD model rats. The rotational behaviour of the rats was determined and the content of dopamine, 3,4 dihydroxyphenylacetic acid and homovanillic acid in the striatum of the rat models was analysed at 4, 8, 12, 16 and 20 weeks after intracerebral transplantation. It was indicated that the grafted genetically modified cells expressing GDNF could substantially reduce the asymmetric rotational behavior of PD rats by 35.2% (P<0.01) after apomorphine administration. The dopamine level in the striatum of PD rats decreased to 1.92±0.15% and increased to 14.5±2.2% (P<0.05) in the experimental group compared with its normal level. The grafted cell could survive for one year in the striatum of PD rats. The present results suggest that transplantation of GDNF gene expressing cultured fibroblasts is efficacious for treatment of PD.